CN104672208A - Synthesis method of (3,5-bistrifluoromethylpyrazolyl)pyridine derivatives - Google Patents
Synthesis method of (3,5-bistrifluoromethylpyrazolyl)pyridine derivatives Download PDFInfo
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- CN104672208A CN104672208A CN201310616275.3A CN201310616275A CN104672208A CN 104672208 A CN104672208 A CN 104672208A CN 201310616275 A CN201310616275 A CN 201310616275A CN 104672208 A CN104672208 A CN 104672208A
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- bis trifluoromethyl
- hydrazine
- hexafluoroacetylacetone
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- 0 C[C@@](C(F)(F)F)(N(c1cccc(Br)n1)N*)O Chemical compound C[C@@](C(F)(F)F)(N(c1cccc(Br)n1)N*)O 0.000 description 1
- PQMFVUNERGGBPG-UHFFFAOYSA-N NNc1cccc(Br)n1 Chemical compound NNc1cccc(Br)n1 PQMFVUNERGGBPG-UHFFFAOYSA-N 0.000 description 1
- QAMFBRUWYYMMGJ-UHFFFAOYSA-N O=C(CC(C(F)(F)F)=O)C(F)(F)F Chemical compound O=C(CC(C(F)(F)F)=O)C(F)(F)F QAMFBRUWYYMMGJ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The invention discloses a method for synthesizing (3,5-bistrifluoromethylpyrazolyl)pyridine derivatives with potential bioactivity. The method comprises the following step: under heating conditions, carrying out substitution/cyclization/dehydration reaction on the raw material 2-bromopyridine derivatives with hydrazine hydrate and hexafluoroacetylacetone to synthesize the (3,5-bistrifluoromethylpyrazolyl)pyridine. Compared with the reported synthesis methods, the method disclosed by the invention has the advantages of accessible raw material, high synthesis efficiency, easy derivation of the product and the like.
Description
Technical field
The present invention relates to a kind of method of preparation (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate.Replace/cyclisation/dehydration reaction with the 2-bromopyridine derivative being easy to prepare for raw material and hydrazine hydrate and hexafluoroacetylacetone, prepare (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate.Compared with the preparation method reported, the present invention has that raw material is easy to get, combined coefficient is high and product is easy to the advantages such as derivatize.
Technical background
(3,5-bis trifluoromethyl pyrazolyl) pyridine derivate is the broad-spectrum N-heterogeneous ring compound of a class, and this kind of material not only has potential biological activity, also can be used for preparing high reactivity composition catalyst or complex luminescent material.They arouse widespread concern as the potential application of medicine and luminescent material, and some has obtained commercial application.Medicine Celecoxib (celecoxib) containing trifluoromethyl pyrazol structure is by Pharmacia and Pfizer's joint development, it is the inhibitor of COX-2 (COX-2), be a kind of widely used analgesic, nearest scientific research personnel finds that it also has effect of prevention lung cancer.Calendar year 2001 patent (U.S.Pat.Appl.Publ., US20010044445) reports the generation that this kind of material can suppress interleukin II, plays a role in the treatment and prevention of relative disease.2006 patent (PCT Int.Appl., WO2006098505) report the potential application of this kind of material in electroluminescent organic material.
Up to now, the method preparing this kind of material mainly first synthesizes the pyrazoles of trifluoromethyl replacement, target product (U.S.Pat.Appl.Publ., US20010044445 and PCT Int.Appl., WO2006098505) is obtained again with heterogeneous ring compound couplings such as pyridines.But for the pyrazoles that bis trifluoromethyl replaces, due to the electrophilic performance that trifluoromethyl is strong, make the nucleophilicity of pyrazoles greatly weaken, aforesaid method is no longer suitable for the pyrazoles preparation that bis trifluoromethyl replaces.The present invention utilizes and is easy to preparation, the 2-bromopyridine derivative of wide material sources is raw material, first the hydrazine derivative that pyridine replaces is prepared, again with hexafluoroacetylacetone through cyclisation/dehydration reaction, efficient synthesis (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate 1.
(3,5-bis trifluoromethyl pyrazolyl) pyridine derivate 1
Summary of the invention
The object of the present invention is to provide that a kind of raw material is easy to get, reaction conditions gentleness, wide adaptability, the method for (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate can be synthesized efficiently.
To achieve these goals, technical scheme of the present invention is as follows:
There is substitution reaction in organic solvent and generate pyridyl replacement hydrazine 4 (reaction formula 1) in 2-bromopyridine derivative 2 and hydrazine hydrate (3), then be that raw material and hexafluoroacetylacetone (5) cyclization occurs generate intermediate product 6 (reaction formula 2) with 4,6 dewater (reaction formula 3) more in acid condition.After reaction terminates, separation purification method carries out product separation and sign routinely, obtains (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate 1.
The feature of technical scheme is:
1,2-bromopyridine derivative 2 is synthon, and its substituent R is bromine atoms or 3，5-dimethylpyrazole base.
2, hydrazine hydrate (3) and hexafluoroacetylacetone (5) are commercial prod, directly can buy use.
3, reaction solvent is one or more organic solvents, and wherein 2-bromopyridine derivative 2 carries out in protic solvent methyl alcohol or propyl carbinol with the reaction of hydrazine hydrate is best; Pyridyl replaces hydrazine 4 to carry out in tetrahydrofuran (THF) or ethanol with the reaction of hexafluoroacetylacetone; 6 dehydrations generate in best one or more in acid solvent acetic acid or the vitriol oil of the reaction of (3,5-bis trifluoromethyl pyrazolyl) pyridine derivates 1 to be carried out.
4, pyridyl replaces hydrazine 4 with the mol ratio of hexafluoroacetylacetone is 1:1-1:10.Wherein, when mol ratio is 1:1.2, reaction effect is best.
5, pyridyl replaces hydrazine 4 with the temperature of reaction of hexafluoroacetylacetone is 50-150 DEG C.Wherein, optimal reaction temperature is 60-100 DEG C.
6, pyridyl replaces hydrazine 4 with the reaction times of hexafluoroacetylacetone is 1-24 hour.Wherein, optimum reacting time is 3-6 hour.
The present invention has the following advantages:
1) (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate 1 purposes is comparatively wide, can be used as potential bioactive molecules, also can be used for the part preparing high reactivity composition catalyst or complex luminescent material.
2) all right derivatize further of (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate 1, thus expand its range of application, the heterocycles such as benzoglyoxaline, oxazoline, tetrahydroglyoxaline and triazine can be converted into as the bromine atoms on pyridine ring.
3) (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate 1 synthetic method is novel, preparation efficiency is high, product application is extensive, be easy to derivatize.
4) 2-bromopyridine derivative 2 wide material sources, are cheaply easy to get or are easy to preparation.
In a word, the present invention utilizes 2-bromopyridine derivative 2 and hydrazine hydrate and the efficient synthetic use of hexafluoroacetylacetonate reactive ketone (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate 1 widely, and synthetic method is novel, preparation efficiency is high and be easy to derivatize.
Embodiment
The present invention, dewaters by reaction formula (1)-(3) and hydrazine hydrate and hexafluoroacetylacetonate reactive ketone for starting raw material with 2-bromopyridine derivative 2, efficient synthesis (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate 1.Contribute to understanding the present invention further by following embodiment, but content of the present invention is not limited to this.
There is substitution reaction and generate pyridyl replacement hydrazine 4(reaction formula 1 in 2-bromopyridine derivative 2 and hydrazine hydrate (3) in organic solvent.Detailed process is: 2-bromopyridine derivative 2(10.0mmol) and hydrazine hydrate (3) (20.0mmol) in 20mL propyl carbinol in 120 DEG C of stirring reactions 12 hours.Be chilled to room temperature, remove Volatile Colstituent under decompression, solid uses water (5mL) and ether (5mL) to wash three times respectively successively, and at 50 DEG C, vacuum-drying obtains target product 4 in 2 hours.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 1
2,6-dibromo pyridine 2a(2.37g, 10.0mmol), the mixture of hydrazine hydrate (20.0mmol) and 20mL propyl carbinol is 120 DEG C of stirring reactions 12 hours.Remove Volatile Colstituent under decompression after being chilled to room temperature, solid uses water (5mL) and ether (5mL) to wash three times respectively successively, and at 50 DEG C, vacuum-drying obtains brown solid 4a for 2 hours is target product (1.25g, yield 67%).Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 2
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, what add in reaction system is the bromo-6-of 2-(3，5-dimethylpyrazole base) pyridine (2b) (2.51g, 10.0mmol).After stopped reaction, obtaining brown solid 4b through same aftertreatment is target product (1.30g, yield 65%).Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.Compound 2b presses literature method (Sun, X.J.; Yu, Z.K.; Wu, S.Z.; Xiao, W.J.Organometallics2005,24,2959) preparation.
Embodiment 3
In 25mL Schlenk reaction flask, add 2-bromo-6-hydrazine pyridine 4a(187mg, 1.0mmol successively), hexafluoroacetylacetone (242mg, 1.2mmol), trifluoroacetic acid (50 μ L) and 15mL tetrahydrofuran (THF), return stirring reacts 5 hours.After reaction terminates, mixture is chilled to room temperature, under decompression, removes Volatile Colstituent, be then separated (elutriant is sherwood oil (60-90 DEG C)/ether, v/v=50:1) with silica gel column chromatography, obtain desired product as white solid 6a(346mg, yield 94%).Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 4
Reactions steps and operation are with embodiment 3, and difference from Example 3 is, 24 hours reaction times.Stopped reaction, obtains target product 6a(346mg through same aftertreatment, yield 94%).Illustrate that the prolongation reaction times is unhelpful to increase target product yield.
Embodiment 5
Reactions steps and operation are with embodiment 3, and difference from Example 3 is, reaction solvent is ethanol.Stopped reaction, obtains target product 6a(147mg through same aftertreatment, yield 40%).Illustrate and use protic solvent to be unfavorable for that target product generates.
Embodiment 6
Reactions steps and operation are with embodiment 3, and difference from Example 3 is, temperature of reaction is 30 DEG C.Stopped reaction, obtains target product 6a(173mg through same aftertreatment, yield 47%).Illustrate that temperature of reaction is too low and be unfavorable for that target product generates.
Embodiment 7
Reactions steps and operation are with embodiment 3, and difference from Example 3 is, temperature of reaction is 50 DEG C.Stopped reaction, obtains target product 6a(313mg through same aftertreatment, yield 85%), illustrate that temperature reduces and be unfavorable for that target product generates.
Embodiment 8
Reactions steps and operation are with embodiment 3, and difference from Example 3 is, reaction solvent is Isosorbide-5-Nitrae-dioxane, temperature of reaction 100 DEG C.Stopped reaction, obtains target product 6a(313mg through same aftertreatment, yield 85%).Illustrate that other ethers also can be used as reaction solvent, but be not optimum response solvent.
Embodiment 9
Reactions steps and operation are with embodiment 3, and difference from Example 3 is, adds acetic acid (50 μ L).Stopped reaction, obtains target product 6a(103mg through same aftertreatment, yield 25%).Illustrate that additive acidity is too weak and be unfavorable for that target product generates.
Embodiment 10
Reactions steps and operation are with embodiment 3, and difference from Example 3 is, does not add trifluoroacetic acid.Stopped reaction, does not obtain target product.Illustrate that trifluoroacetic acid is absolutely necessary smoothly to reaction.
Embodiment 11
Reactions steps and operation are with embodiment 3, and difference from Example 3 is, adds trifluoroacetic acid (25 μ L).Stopped reaction, obtains target product 6a(202mg through same aftertreatment, yield 55%).Illustrate that trifluoroacetic acid add-on is very few and be unfavorable for that target product generates.
Embodiment 12
Reactions steps and operation are with embodiment 3, and difference from Example 3 is, hexafluoroacetylacetone add-on is 202mg(1.0mmol).Stopped reaction, obtains target product 6a(280mg through same aftertreatment, yield 76%).Illustrate and use the hexafluoroacetylacetone of equimolar amount can not make the complete conversion reaction of raw material 4a, be unfavorable for that target product generates.
Embodiment 13
Reactions steps and operation are with embodiment 3, and difference from Example 3 is, that add in reaction system is 2-(3，5-dimethylpyrazole)-6-hydrazine pyridine 4b(201mg, 1.0mmol).Stopped reaction, obtains desired product as white solid 6b(377mg through same aftertreatment, yield 96%).Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 14
In 25mL reaction flask, add 6a(361mg, 1.0mmol successively), the vitriol oil (0.25mL) and 15mL acetic acid, stirring reaction 4 hours at 120 DEG C.After reaction terminates, mixture is chilled to room temperature, removes Volatile Colstituent under decompression, add the washing of 25mL saturated sodium bicarbonate aqueous solution, aqueous layer with ethyl acetate extracts (3 × 10mL), separates organic phase.Organic phase merges rear anhydrous sodium sulfate drying, filtration.Remove Volatile Colstituent under decompression, be then separated (elutriant is sherwood oil (60-90 DEG C/ether, v/v=40:1), obtains desired product as white solid 1a(311mg, yield 86%) with silica gel column chromatography.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 15
Reactions steps and operation are with embodiment 14, and be with embodiment 14 difference, that add in reaction system is 6b(393mg, 1.0mmol).Stopped reaction, obtains desired product as white solid 1b(330mg through same aftertreatment, yield 88%).Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Typical compound characterization data
(3,5-bis trifluoromethyl pyrazolyl) pyridine derivate (1a), white solid, fusing point 45-46 DEG C.
1H NMR(CD
3COCD
3,400MHz,23℃)δ8.06(t,J=7.9Hz,1H),7.98(d,J=8.0Hz,1H),7.79(d,J=7.7Hz,1H),7.55(s,1H);
13C{
1H}NMR(CD
3COCD
3,100MHz,23℃)δ149.9(s),143.1(q,J=39.8Hz),142.2(s),139.0(s),134.0(q,J=42.2Hz),128.8(s),120.4(q,J=267.0Hz),119.1(q,J=267.0Hz),115.5(s),109.9(s);
19F{
1H}NMR(CD
3COCD
3,100MHz,23℃)δ-59.4(s),-64.0(s)。C
10h
4brF
6n
3hRMS theoretical value ([M
+]): 358.9493; Measured value: 358.9495.
(3,5-bis trifluoromethyl pyrazolyl) pyridine derivate (1b), white solid, fusing point 51-52 DEG C.
1H NMR(CD
3COCD
3,400MHz,23℃)δ8.20(t,J=7.8Hz,1H),8.12(d,J=8.2Hz,1H),7.66(d,J=7.7Hz,1H),7.58(s,1H),6.06(s,1H),2.56(s,3H),2.23(s,3H);
13C{
1H}NMR(CD
3COCD
3,100MHz,23℃)δ152.6(s),150.4(s),148.5(s),142.9(q,J=39.3Hz),141.7(s),133.5(q,J=41.4Hz),120.6(q,J=266.9Hz),119.2(q,J=267.2Hz),117.1(s),116.0(s),109.7(s),108.6(s),13.12(s),13.11(s);
19F{
1H}NMR(CD
3COCD
3,100MHz,23℃)δ-58.9(s),-63.7(s)。C
15h
11f
6n
5hRMS theoretical value ([M
+]): 375.0919; Measured value: 375.0926.
2-bromo-6-hydrazine pyridine (4a), brown solid, fusing point 109-111 DEG C.
1H NMR(CD
3COCD
3,400MHz,23℃)δ8.63(s,1H),7.44(t,J=8.3and J=7.4Hz,1H),7.09(d,J=8.3Hz,1H),6.83(d,J=7.4Hz,1H),4.05(s,2H);
13C{
1H}NMR(CD
3COCD
3,100MHz,23℃)δ158.2(s),140.2(s),139.1(s),117.4(s),105.3(s)。C
5h
6brN
3hRMS theoretical value ([M
+]): 186.9745; Measured value: 186.9749.
2-(3，5-dimethylpyrazole base)-6-hydrazine pyridine (4b), brown solid, fusing point 160-162 DEG C.
1H NMR(CD
3COCD
3,400MHz,23℃)δ7.48(t,J=8.2Hz and J=7.9Hz,1H),7.06(d,J=8.2Hz,1H),6.43(d,J=7.7Hz,1H),6.24(s,1H),5.92(s,1H),3.90(s,2H),2.53(s,3H),2.24(s,3H);
13C{
1H}NMR(CD
3COCD
3,100MHz,23℃)δ159.9(s),151.8(s),149.5(s),140.9(s),139.5(s),108.6(s)105.6(s),103.7(s),14.5(s),13.6(s)。C
10h
13n
5hRMS theoretical value ([M
+]): 203.1171; Measured value: 203.1174.
(3,5-bis trifluoromethyl-4,4-dihydro-5-hydroxypyrazoles base) pyridine derivate (6a), white solid, fusing point 110-112 DEG C.
1H NMR(CD
3COCD
3,400MHz,23℃)δ7.80(t,J=8.0Hz,1H),7.46(d,J=9.6Hz,2H),7.34(d,J=7.7Hz,1H),3.95(d,J=19.6Hz,1H),3.65(d,J=19.6Hz,1H);
13C{
1H}NMR(CD
3COCD
3,100MHz,23℃)δ154.5(s),141.2(q,J=39.5Hz),137.8(s),123.2(q,J=284.5Hz),122.1(s),120.1(q,J=226.7Hz),110.3(s),94.3(q,J=34.2Hz),42.0(s);
19F{
1H}NMR(CD
3COCD
3,100MHz,23℃)δ-60.0(s),-87.7(s)。C
10h
6brF
6n
3hRMS the theoretical value ([M of O
+]): 376.9598; Measured value: 376.9595.
(3,5-bis trifluoromethyl-4,4-dihydro-5-hydroxypyrazoles base) pyridine derivate (6b), white solid, fusing point 124-126 DEG C.
1H NMR(CD
3COCD
3,400MHz,23℃)δ7.95(t,J=8.1Hz,1H),7.82(s,1H),7.50(d,J=8.0Hz,1H),7.32(d,J=8.2Hz,1H),6.06(s,1H),3.91(d,J=19.6Hz,1H),3.61(d,J=19.6Hz,1H),2.56(s,3H),2.21(s,3H);
13C{
1H}NMR(CD
3COCD
3,100MHz,23℃)δ153.1(s),150.8(s),149.7(s),140.9(s),140.6(s),139.9(q,39.0Hz),123.4(q,J=284.4Hz),120.1(q,J=267.7Hz),111.1(s),109.5(s),109.0(s),94.4(q,J=33.4Hz),42.2(s),12.77(s),12.73(s);
19F{
1H}NMR(CD
3COCD
3,100MHz,23℃)δ-68.0(s),-81.0(s)。C
15h
13f
6n
5hRMS the theoretical value ([M of O
+]): 393.1024; Measured value: 393.1029.
Claims (7)
1. the synthetic method of one kind (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate, (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate (1) structural formula is as follows,
Substituent R is bromine atoms or 3，5-dimethylpyrazole base;
It is characterized in that: with 2-bromopyridine derivative (2) for starting raw material, generate pyridyl replace hydrazine (4) by reacting with hydrazine hydrate (3), cyclisation/dehydration reaction is there is again with hexafluoroacetylacetone (5), generate (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate (1);
The structure of 2-bromopyridine derivative (2) is as follows,
Substituent R is bromine atoms or 3，5-dimethylpyrazole base;
Synthetic route, as shown in following reaction formula, is divided into three steps to carry out,
2., according to synthetic method according to claim 1, it is characterized in that:
Wherein: 2-bromopyridine derivative (2) is 2,6-dibromo pyridine or the bromo-6-(3 of 2-, 5-dimethyl pyrazole base) pyridine, 2-bromopyridine derivative (2) and the reaction solvent of hydrazine hydrate (3) they are the mixed solvent of one or two or more kinds in methyl alcohol, propyl carbinol or toluene; 2-bromopyridine derivative (2) is 1:1-1:10 with the mol ratio of hydrazine hydrate (3); Temperature of reaction is 20-150 DEG C; Reaction times is 1-24 hour.
3. according to synthetic method according to claim 2, it is characterized in that: 2-bromopyridine derivative 2 carries out in protic solvent methyl alcohol or propyl carbinol with the reaction of hydrazine hydrate (3) is best;
2-bromopyridine derivative 2 and hydrazine hydrate (3) react, and its optimum mole ratio is 1:2-1:4;
2-bromopyridine derivative 2 and hydrazine hydrate (3) react, and optimal reaction temperature is 100-150 DEG C;
2-bromopyridine derivative 2 and hydrazine hydrate (3) react, and optimum reacting time is 6-15 hour.
4., according to synthetic method according to claim 1, it is characterized in that:
Pyridyl replacement hydrazine (4) and the reaction solvent of hexafluoroacetylacetone (5) are the mixed solvent of one or two or more kinds in ethanol, tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane; It is 1:1-1:5 that pyridyl replaces hydrazine (4) with the mol ratio of hexafluoroacetylacetone (5); Temperature of reaction is 20-120 DEG C; Reaction times is 2-12 hour.
5. according to synthetic method according to claim 4, it is characterized in that: pyridyl replaces hydrazine 4 to carry out in ethanol or tetrahydrofuran (THF) with the reaction of hexafluoroacetylacetone (5) is best;
Pyridyl replaces hydrazine 4 and reacts with hexafluoroacetylacetone (5), and its optimum mole ratio is 1:1.1-1:1.5;
Pyridyl replaces hydrazine 4 and reacts with hexafluoroacetylacetone (5), and optimum temps is 60-100 DEG C;
Pyridyl replaces hydrazine 4 and reacts with hexafluoroacetylacetone (5), and optimum reacting time is 3-6 hour.
6., according to synthetic method according to claim 1, it is characterized in that:
(3,5-bis trifluoromethyl-4,4-dihydro-5-hydroxy-pyrazole base) to generate the reaction solvent of (3,5-bis trifluoromethyl pyrazolyl) pyridine and its derivatives (1) be the mixed solvent of one or two or more kinds in acetic acid, trifluoroacetic acid or the vitriol oil in pyridine (6) dehydration; Temperature of reaction is 50-150 DEG C; Reaction times is 1-12 hour, and after reaction terminates, separation purification method carries out product separation routinely, obtains (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate 1.
7. according to synthetic method according to claim 2, it is characterized in that: (3,5-bis trifluoromethyl-4,4-dihydro-5-hydroxy-pyrazole base) pyridine (6) dehydration generate (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate (1) reaction one or two or more kinds in acid solvent acetic acid or the vitriol oil best mixed solvent in carry out;
The dehydration of (3,5-bis trifluoromethyl-4,4-dihydro-5-hydroxy-pyrazole base) pyridine (6) generates the reaction of (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate (1), and optimal reaction temperature is 80-140 DEG C;
The dehydration of (3,5-bis trifluoromethyl-4,4-dihydro-5-hydroxy-pyrazole base) pyridine (6) generates the reaction of (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate (1), and optimum reacting time is 2-8 hour.
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| CN106810539A (en) * | 2015-11-27 | 2017-06-09 | 中国科学院大连化学物理研究所 | A kind of phenyl bridged pyrazolate base benzimidizole derivatives and preparation method thereof |
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| CN101142223A (en) * | 2005-03-16 | 2008-03-12 | 富士胶片株式会社 | Platinum complex compound and organic electroluminescent device |
| CN102939282A (en) * | 2010-04-16 | 2013-02-20 | Ac免疫有限公司 | Novel compounds for the treatment of diseases associated with amyloid or amyloid-like proteins |
| CN103214466A (en) * | 2013-03-25 | 2013-07-24 | 南京工业大学 | Methyl arylpyrazole fluorouracil compounds, and preparation method and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010044445A1 (en) * | 1999-04-08 | 2001-11-22 | Bamaung Nwe Y. | Azole inhibitors of cytokine production |
| CN101142223A (en) * | 2005-03-16 | 2008-03-12 | 富士胶片株式会社 | Platinum complex compound and organic electroluminescent device |
| CN102939282A (en) * | 2010-04-16 | 2013-02-20 | Ac免疫有限公司 | Novel compounds for the treatment of diseases associated with amyloid or amyloid-like proteins |
| CN103214466A (en) * | 2013-03-25 | 2013-07-24 | 南京工业大学 | Methyl arylpyrazole fluorouracil compounds, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106810539A (en) * | 2015-11-27 | 2017-06-09 | 中国科学院大连化学物理研究所 | A kind of phenyl bridged pyrazolate base benzimidizole derivatives and preparation method thereof |
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